Chlamydiae are obligate intracellular microorganisms which parasitize eukaryotic cells and are ubiquitous throughout the animal kingdom. Members of the chlamydial genus are considered bacteria with a unique biphasic developmental cycle having distinct morphological and functional forms. This developmental growth cycle alternates between 1) intracellular life forms, of which two are currently recognized, a metabolically-active, replicating organism known as the reticulate body (RB) and a persistent, non-replicating organism known as the cryptic phase; and 2) an extracellular life form that is an infectious, metabolically-inactive form known as the elementary body (EB).
EBs are small (300-400 nm) infectious, spore-like forms which are metabolically inactive, non-replicating, and found most often in the acellular milieu. EBs are resistant to a variety of physical insults such as enzyme degradation, sonication and osmotic pressure. This physical stability is thought to be a result of extensive disulfide cross-linking of the cysteine-rich major outer membrane protein (MOMP) (Bavoil et al., Infection and Immunity, 44:479-485 (1984); Hackstadt et al., Journal of Bacteriology, 161:25-31 (1985); Hatch et al., Journal of Bacteriology, 165:379-385 (1986); Peeling et al., Infection and Immunity, 57:3338-3344 (1989); J. C. A. Bardwell, Molecular Microbiology, 14:199-205 (1994); and T. P. Hatch, Journal of Bacteriology, 178:1-5 (1993)). Under oxidizing conditions in the acellular milieu of the host, the outer membrane of EBs is relatively impermeable as well as resistant to inactivation. EBs are thus well suited to survive long enough outside of their hosts to be transmitted to a new host in the form of a droplet nuclei (Theunissen et al., Applied Environmental Microbiology, 59:2589-2593 (1993)) or a fomite (Fasley et al., The Journal of Infectious Diseases, 168:493-496 (1993)).
Infection by members of the genus Chlamydiae induces a significant inflammatory response at the cellular level. For example, genital lesions produced by Chlamydia trachomatis frequently elicit a vigorous influx of lymphocytes, macrophages, and plasma cells, suggesting the development of humoral and cellular immunity. Yet, clinically, the initial infection is frequently varied in symptomatology and may even be asymptomatic. Once fully established, the Chlamydia are difficult to eradicate, with frequent relapse following antibiotic therapy. Evidence also indicates that the Chlamydia may become dormant and are then shed in quantities too few to reliably detect by culture.
Chlamydia pneumoniae (hereinafter “C. pneumoniae”) is the most recent addition to the genus Chlamydiae and is isolated from humans and currently is recognized as causing approximately 10 percent of community acquired cases of pneumonia (Grayston et al., J. Inf. Dis. 161:618-625 (1990)). This newly recognized pathogen commonly infects the upper and lower respiratory tract and is now recognized as ubiquitous in humans. C. pneumoniae is well-accepted as a human pathogen that may be difficult to eradicate by standard antibiotic therapy (Hammerschlag et al., Clin. Infect. Dis. 14:178-182 (1992)). C. pneumoniae is known to persist as a silent or mildly symptomatic pathogen, resulting in a chronic, persistent infection (J. Schacter, In: Baun A L, eg. Microbiology of Chlamydia, Boca Raton, Fla., CRC Press, 1988, pp. 153-165).
The current therapy for suspected/confirmed C. pneumoniae infection is with a short course (e.g., 2-3 weeks) of a single antibiotic. C. pneumoniae is susceptible in vitro to tetracyline, erythromycin, clarithromycin, and fluoroquinolones such as ofloxacin and sparfloxacin (Kuo et al., Antimicrob Agents Chemother 32:257-258 (1988); Welsh et al., Antimicrob Agents Chemother 36:291-294 (1992); Chirgwin et al., Antimicrob Agents Chemother 33:1634-1635 (1989); Hammerschlag et al., Antimicrob Agents Chemother 36:682-683 (1992); Hammerschlag et al., Antimicrob Agents Chemother 36:1573-1574); M. R. Hammerschlag, Antimicrob Agents Chemother 38:1873-1878 (1994); M. R. Hammerschlag, Infect. Med. pp. 64-71 (1994)). Despite this demonstration of in vitro susceptibility, C. pneumoniae infections may relapse following antibiotic therapy with these agents. In vitro studies on the persistence of Chlamydiae despite specific and appropriate antibiotic therapy have suggested that the presence of antibiotics promotes the formation of an intracellular, non-replicative state (Beatty et al., Microbiol. Rev. 58:686-699 (1994)), typically referred to as the latent or cryptic phase. This change can be thought of as a stringent response and is seen also with nutrient starvation and exposure to γ-interferon. Removal of the stressful influence allows the organism to resume replication. Thus, in this way, the organism can escape current antibiotic therapy used in clinical practice.
In view of the chronic and persistent nature of chlamydial infections, there is a need for reliable, accurate methods for diagnosis of pathogenic infection as well as therapeutic approaches to manage the infection. Due to the highly infective nature of Chlamydia EBs and their ability to reinfect cells, there is also a need for antichlamydial therapy which totally eradicates this pathogen, thereby preventing the long term sequelae of such chronic infections.